Báo cáo khoa học: "Lynch syndrome: still not a familiar picture" pptx

For Lynch syndrome, these features can be found in the Amsterdam and Bethesda criteria.. The most common of the known CRC predisposing syndromes is Lynch syndrome previously also annotat

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Open Access

Case report

Lynch syndrome: still not a familiar picture

Frederik J Hes

Address: Center for Human and Clinical Genetics (CHKG), Department of Clinical Genetics, Leiden University Medical Center (LUMC), RC

Leiden, The Netherlands

Email: Frederik J Hes - f.j.hes@lumc.nl

Abstract

Background: Germ line mutations in mismatch repair genes underlie Lynch syndrome and

predispose carriers for colorectal carcinoma and malignancies in many other organ systems

Case presentation: A large Lynch syndrome family with 15 affected family members and

involvement in 7 organs is reported It illustrates a lack of awareness and knowledge about this

hereditary tumor syndrome among doctors as well as patients None of the described family

members underwent presymptomatic screening on the basis of the family history

Conclusion: Hereditary features, like young age at diagnosis, multiple tumors in multiple organs

and a positive family history, should lead to timely referral of suspected cases for genetic counseling

and diagnostics For Lynch syndrome, these features can be found in the Amsterdam and Bethesda

criteria Subsequently, early identification of mutation carriers might have diminished, at least in

part, the high and early morbidity and mortality observed in this family

Background

Colorectal carcinoma (CRC) is an important cause of

can-cer-related death in the Western world The lifetime risk is

about 5% and is rising [1] Currently, about 5% of all CRC

cases can currently be explained by known inherited

tumor syndromes The most common of the known CRC

predisposing syndromes is Lynch syndrome (previously

also annotated as hereditary non-polyposis colorectal

can-cer; HNPCC) which is characterized by the development

of CRC, endometrial cancer and various other cancers [2]

This tumor syndrome is caused by a mutation in one of

the mismatch repair (MMR) genes: MLH1, MSH2, MSH6

or PMS2 Tumors observed in Lynch syndrome families

are diagnosed at an unusual early age and may be

multi-ple The MMR-defect leads to instability at microsatellites

of tumor-DNA that is called microsatellite instability

(MSI) Subsequently, with immunohistochemical (IHC-)

analysis using antibodies against the four MMR-proteins,

loss of protein expression of the causative gene can be demonstrated In order to standardize clinical and basic research the Amsterdam criteria were first published in

1991 and revised in 1999 [3,4] In 1997, the Bethesda guidelines were developed to select patients that should be tested for MSI and IHC These guidelines were revised in

2004 [5,6] The revised Amsterdam criteria and Bethesda guidelines are shown in Table 1 These guidelines have enabled the recognition of vast numbers of affected fami-lies, and germline mutation analysis of the MMR-genes has led to identification of many (asymptomatic) family members at risk for Lynch syndrome However, this case report illustrates a lack of awareness about this hereditary tumor syndrome among doctors as well as patients

Case presentation

In November 2006, a 56-year old woman (III-1 in pedi-gree, Figure 1) visited our clinic for genetic counseling

Published: 20 February 2008

World Journal of Surgical Oncology 2008, 6:21 doi:10.1186/1477-7819-6-21

Received: 18 December 2007 Accepted: 20 February 2008 This article is available from: http://www.wjso.com/content/6/1/21

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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because she was worried about the many cases of cancer

that had occurred in her family The direct reason for her

visit was the recent death of her 39-year old son (IV-1)

with a symptomatic, and already metastasized, rectal

ade-nocarcinoma The counselee had been diagnosed with an

endometrial and a sigmoid carcinoma at age 53- and

54-years old, respectively She reported her overwhelming

family history, which easily fulfilled the criteria that

ena-ble selection of families that are at risk for Lynch

syn-drome (Table 1) Subsequent IHC-analysis on archival

tumor material of her sigmoid carcinoma demonstrated

abrogation of the MSH2 and MSH6 proteins, which is

typ-ically associated with a germline MSH2 mutation

Multi-plex ligation-dependent probe amplification (MLPA), in

DNA extracted from peripheral lymphocytes, identified

an entire MSH2 gene deletion (exons 1–16) and

con-firmed the diagnosis of Lynch syndrome

In retrospect, some doctors had indeed signaled notewor-thy features in this family First, in 1979, a gynecologist who was treating patient II-6 consulted a colleague about the very early onset of endometrial carcinoma His col-league reassured him at that time that the age at presenta-tion, 41 years old, was not in fact very rare Second, in

2005, a gastroenterologist spoke of possible HNPCC in patient III-2, who was diagnosed with carcinoma of the papilla of Vater after she had developed three separate colon carcinomas, but no further action was taken Third,

in 2006, an oncologist treating patient IV-1 suggested MSI testing on tumor material after his mother (III-1) had expressed her concern about the family history, but did not proceed

Table 1: Amsterdam criteria II and revised Bethesda guidelines.

Amsterdam criteria II

There should be at least three relatives with colorectal cancer (CRC) or with a Lynch syndrome associated cancer: cancer of the endometrium, small bowel, ureter or renal pelvis.

- one relative should be a first-degree relative of the other two;

- at least two successive generations should be affected,

- at least one tumor should be diagnosed before the age of 50 years,

- FAP should be excluded in the CRC case if any,

- tumours should be verified by histopathological examination.

Revised Bethesda guidelines

1 CRC diagnosed in a patient aged <50 years.

2 Presence of synchronous, metachronous colorectal, or other Lynch syndrome-related tumours*, regardless of age.

3 CRC with MSI-high phenotype diagnosed in a patient aged < 60 years.

4 Patient with CRC and a first-degree relative with a Lynch syndrome-related tumor, with one of the cancers diagnosed aged <50 years.

5 Patient with CRC with two or more first-degree or second-degree relatives with a Lynch syndrome-related tumor, regardless of age.

*Lynch syndrome related tumours include colorectal, endometrial, stomach, ovarian, pancreas, ureter, renal pelvis, biliary tract, and brain tumours, sebaceous gland adenomas and keratoacanthomas and carcinoma of the small bowel

Pedigree of a Lynch syndrome family, showing organ systems and age of diagnosis, see legend

Figure 1

Pedigree of a Lynch syndrome family, showing organ systems and age of diagnosis, see legend Year, year of

diag-nosis/diagnoses; asterisk, anamnestically obtained information; urinary tract, urothelial carcinoma of renal pelvis or ureter; skin, keratoacanthoma; asc., ascending colon; transv., transverse colon; desc., descending colon

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Discussion

This family is a fine example of the plethora of tumors

that may occur in Lynch syndrome and demonstrates why

the term Lynch syndrome is preferred nowadays over

HNPCC (hereditary non-polyposis colorectal cancer),

which only refers to CRC The organ involvement in this

family included seven organ systems: colon, uterus, skin,

stomach, urinary tract, pancreas and hepatobiliary system

The manifestation of keratoacanthoma in this family

ena-bled a sub-classification to Muir Torre syndrome (MTS)

MTS is a variant of Lynch syndrome and germline

muta-tions in the three main Lynch syndrome genes (MLH1,

MSH2 and MSH6) have been identified in MTS families

[7,8] Keratoacanthoma should be regarded as one of the

tumors that lie in the constellation of Lynch syndrome

but their manifestation could depend on modifier genes

and/or environmental factors

This case report shows a considerable delay in diagnosing

Lynch syndrome which negatively influenced the

man-agement of many family members None of the family

members underwent presymptomatic screening on the

basis of the family history, while clinical surveillance has

been shown to decrease mortality in Lynch syndrome

families [9] Remarkably, in none of the medical reports

we obtained was a family history reported extending

fur-ther than first-degree relatives

Conclusion

This family clearly illustrates a lack of awareness about a

hereditary tumor syndrome among doctors as well as

patients In general, it is prudent to be aware of classic

hereditary features, like young age at diagnosis, multiple

tumors in multiple organs and a positive family history,

and to refer suspected cases for genetic counseling More

specifically, these features can be found in the Amsterdam

and Bethesda criteria (Table 1) Subsequently, the

identi-fication of at-risk persons will optimize the timing and

efficiency that surveillance and treatment are carried out

Abbreviations

CRC: colorectal cancer; HNPCC: hereditary

non-polypo-sis colorectal cancer; IHC: immunohistochemistry; MSI:

microsatellite instability; MLPA: multiplex

ligation-dependent probe amplification; MTS: Muir Torre

syn-drome

Competing interests

The author(s) declare that they have no competing

inter-ests

Authors' contributions

FJH contributed to conception and design, acquisition of

data, analysis and interpretation of data He also drafted

the manuscript and gave final approval of the version to

be published

Acknowledgements

Written permission was obtained from the index-patient for publication of this case report The author should like to thank Dr C.M.J Tops for carry-ing out the molecular genetic studies and Prof H Morreau for immunohis-tochemical analysis.

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